The objective of this program is to determine structural, functional, genetic and evolutionary relationships of human immunoglobulins by study of pathological proteins produced by patients with multiple myeloma, macroglobulinemia, and related lymphomas. Emphasis is on determination of the complete covalent structure of kappa and lambda light chains and of IgM and IgA1 (already accomplished), IgA2 and its allotypes (nearly completed), and IgD (just begun). Specific aims are: (1) to relate these structures to subgroup, subclass, class, and biological differences among normal and pathological immunoglobulins, (2) to correlate primary structure, conformation and biological properties such as complement fixation and cytotropic specificity, (3) to relate the structure of proteins from individual patients to idiopathic differences in physical and biological properties, and (4) to interpret the significance of the findings for antibody specificity, and evolution of immunoglobulins. New directions include preparation of biologically active fragments of IgM and IgA1 and study of their conformation and activity by specific site labeling, proton and 13C-NMR, circular dichroism, and computer analysis of structural homology and of relationships between primary and three-dimensional structure. Another goal is to facilitate development of more specific immunochemical reagents for classification and quantitation of immunoglobulins in normal and pathological sera, for detection in tissues, and as cell surface markers.